tbuckley/cabot-search huggingface dataset:
The use of clinical impact of the breast cancer intrinsic subtype-Prosigna assay for adjuvant treatment decision in early breast cancer with hormone receptor positive and HER-2 negative Middle East women.
Authors: Jamal Zidan, Michelle Leviov, Iryna Kuchuk, Gil Bar-Sela, Ayelet Shai, Olga Kazarin, Nasralla Suheil
Journal: Journal of Clinical Oncology (2022)

e12527 Background: Clinico-pathological evaluations of intrinsic subtypes by immunohistochemistry (IHC) are routinely used for treatment decision in patients with early-stage breast cancer (EBC). The Prosigna (PAM50) gene signature, is validated test measures the expression levels of 50 genes from formalin-fixed paraffin-embedded (FFPE) tumor samples. It permits intrinsic subtype classification of tumor and prognostic test of risk of recurrence (ROR) score. The objectives of this study were to evaluate the impact of Prosigna results on type of adjuvant treatment in EBC, to overcome disparities by comparing the results on different ethnicity groups in Israel and to asses physicians treatment decision before and after Prosigna results. Methods: This prospective, observational study was carried out in 7 Medical Centers at Northern Israel. Postmenopausal women with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative invasive EBC were enrolled. Physicians completed treatment confidence questionnaires prior to and after receiving Prosigna test results. Only EBC : T 1-2, N0 and N1 were included. Results: Between May 2018 and April 2021, 238 women were enrolled, 204 patients are eligible for this analysis. Ashkenazi Jews were 38%, Sephardi Jews 32% and 30% were Palestinian Arab women. Mean age was 65.28 years. T1 was diagnosed in 82.3%, T2 in 17.3% and N1 in 22.4% of pts. At time of diagnosis tumor subtypes were categorized based on IHC as Luminal A in 50%, 54.4%, 59.5% and Luminal B in 50%, 44.6% and 40.5% of Sephardi, Ashkenazi and Arab patients retrospectively. Intrinsic tumor subtypes detected by the Prosigna test were Luminal A in 63.8%, 71%, 74.3% and Luminal B in 34.5% (+1.7% basal like), 29% and 25.7% respectively. No significant different between these groups. Overall 50.5% of pts were low risk, 26% intermediate risk and 23.5% high risk due to Prosigna results. Following Prosigna results 23.4% of the physicians changed their treatment recommendation. Conclusions: To our knowledge this is the first study using Prosigna test in Middle East women with early breast cancer. The use of Prosigna results led to a 23.4% change in adjuvant treatment decision. The results of this prospective study is similar to the data published in other studies in the literature. The intrinsic tumor subtypes and risk of recurrence detected by Prosigna adds to the physicians' confidence in the choice of treatment type. Prosigna test was additive for understanding the biology and for adjuvant treatment choice in both Jewish and Palestinian women in Israel.
ETMR-15. Central Nervous System Embryonal Tumor with EWSR1 translocation: Evolving changes in histology, sequencing, and epigenetics at relapse in 2 patients and potential treatment implications
Authors: Mary Littrell, Kevin Bielamowicz, Murat Gokden, Sateesh Jayappa, Gregory Albert
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Histologically diagnosed embryonal tumors (ET) of the central nervous system (CNS) in the pediatric population represent a group of aggressive malignancies with historically poor prognoses. Immunohistochemistry (IHC) and cytogenetics refined tumor classification and improved treatment strategies. Modern advancements in molecular methods including methylation profiling provide further delineation of distinct ET subclasses. CASE DESCRIPTION: We present two cases with initial diagnosis of a CNS embryonal tumor with EWSR1 rearrangement. Relapsed tissue in both cases displayed acquisition of INI-1 loss consistent with atypical teratoid/rhabdoid tumor (AT/RT). The first case presented at 14 months of age with vomiting and altered mental status. Imaging revealed right frontal lobe hemorrhagic mass with signs of increased intracranial pressure; pathology returned as a CNS embryonal tumor with EWSR1-PLAGL1 translocation. Patient ultimately experienced multiple relapses with tumor sample each with INI-1 loss. The second case presented at 11 months of age with new onset seizures and was found to have right frontal tumor; pathology returned as CNS embryonal tumor with EWSR1-PLAGL1 translocation. Patient experienced recurrence in original tumor bed and pathology was consistent with malignant recurrence with INI-1 loss. Methylation profiling for diagnostic samples in both patients was consistent with ET not otherwise specified, while methylation profiling of relapsed tissue in both cases was consistent with AT/RT. EWSR1 translocation was persistent from diagnostic to relapsed samples. CONCLUSION/DISCUSSION: These cases illustrate the need for ongoing analysis in patients with CNS primitive neuroectodermal tumors and EWSR1 rearrangements, and the unique role of molecular studies in relapsed tissue. The emergence of treatment resistance in a subpopulation of cells more consistent with AT/RT suggests these patients could benefit from upfront and experimental treatment approaches for AT/RT.
Prognostic value of CA 19-9 and carcinoembrionic antigen (CEA) in duodenal adenocarcinoma (DA): An institutional retrospective cohort study.
Authors: Ellery Altshuler, William King, Raymond Richhart, Keegan Hones, Akash Mathavan, Akshay Mathavan, Daniel F. Leach, Yasmeen Murtaza, Jimmy Lee, Denise Manfrini, Mohit Mathavan, Zahara Chowdhury, Sherise C. Rogers, Ibrahim Nassour, Brian Hemendra Ramnaraign, Ilyas Sahin, Aaron J Franke, Thomas J. George, Steven J. Hughes, Jesus C. Fabregas
Journal: Journal of Clinical Oncology (2022)

e16306 Background: Duodenal adenocarcinoma (DA) is a rare malignancy with poor outcomes. Tumor markers are used to assess disease response and to monitor for recurrence. Specifically, CA-19-9 and CEA have been validated for use in pancreatic cancer and colorectal cancer, respectively. However, these tumor markers have never been validated in patients with DA. We aim to assess the association of these biomarkers with clinical outcomes in patients with DA. Methods: This is a retrospective cohort study. After obtaining IRB approval (IRB202102705), we accessed the University of Florida medical records of patient treated for DA from January 1, 2006, until December 31, 2021. CA 19-9 and CEA were collected as continuous variables and were analyzed as binary variables: normal vs. high, using the maximum normal value as a cut-off (normal CA 19-9 &lt; = 35 U/ml; CEA &lt; = 3 ng/ml). Analysis was conducted using Kaplan Meyer curves, log-rank test and Cox proportional hazards model. Results: A total of 68 patients were included in the final analysis. Median age was 67 years and median follow-up was 22.2 months. CA 19-9 and CEA were elevated in 36.8% and 48.5% of patients, respectively. Patients with an elevated CA 19-9 had a median overall survival (OS) of 8.5 months vs. 27.4 months in patients with normal levels (HR 1.67; 95%CI 0.94–2.99; p = 0.081). Patients with an elevated CEA had a median OS of 13.4 months vs. 16.8 months in patients with normal level normal levels (HR 1.43; 95%CI 0.81–2.52; p value = 0.221). In a sensitivity analysis, a concomitant elevation of both tumoral markers was significantly associated with worsened OS (HR 1.9; 95%CI 1.05–3.06; p = 0.035). Conclusions: In patients with duodenal adenocarcinoma, elevation of both CA 19-9 and CEA was associated with a statistically significant worse overall survival. CA 19-9 level had a higher prognostic impact on OS than CEA levels. To our knowledge, this is the first study to evaluate the role of CA 19-9 and CEA in patients with DA. Further research is required for validation.[Table: see text]
Trial in progress: Durvalumab and olaparib for the treatment of prostate cancer in men predicted to have a high neoantigen load.
Authors: Alexandra Sokolova, Roman Gulati, Heather H. Cheng, Tomasz M. Beer, Julie N Graff, Melanie Amador, Andrea Toulouse, Kamilah Taylor, Shawna Bailey, Steven Smith, Shaadi Tabatabaei, Ryan Sinit, Rachel Slottke, Jacqueline Vuky, Todd Yezefski, Petros Grivas, Evan Y. Yu, Michael Thomas Schweizer
Journal: Journal of Clinical Oncology (2022)

TPS5099 Background: Approximately 30% of patients (pts) treated with definitive surgical and/or radiation therapy for localized prostate adenocarcinoma develop biochemical recurrence (BCR). The optimal time to initiate androgen deprivation therapy (ADT) for such patients is controversial and depends on patient and provider preference, absolute PSA value, and PSA doubling time (PSADT), which has been associated with time to metastasis. Because the time from BCR to metastasis can be long in many cases, strategies allowing pts to avoid ADT while extending metastasis-free survival are desirable. Prior studies have shown that a high tumor neoantigen load correlates with response to anti-PD(L)1. We hypothesized that PARP inhibitor-induced genomic instability may sensitize tumors to anti-PD(L)1 through: i) increasing mutational burden and subsequent tumor neoantigen formation, and/or ii) through activation of other immunogenic pathways (e.g. the STING pathway). This trial investigates an ADT-sparing approach for men predicted to have high neoantigen load and who have BCR prostate cancer. Methods: This is a phase 2 clinical trial testing durvalumab (1500 mg IV every 4 weeks) and olaparib (300 mg PO twice a day) (one cycle = 4 weeks) in men with BCR (PSADT≤10 months) whose tumors are predicted to have high neoantigen load based on: biallelic CDK12 mutations (Cohort A), mismatch repair deficiency (MMRd)/high microsatellite instability (MSI-H) (Cohort B), or loss of function mutations in homologous recombination repair (HRR) genes (Cohort C). Cohorts A and B will receive 3 cycles of durvalumab followed by 3 cycles of the combination of durvalumab and olaparib. Given the proven efficacy of olaparib in prostate cancer patient whose tumors posses an HRR gene mutation, Cohort C will receive 6 full cycles of the combination. Ten patients will be enrolled in each cohort (total n = 30) at two collaborating sites. This study was designed to provide preliminary efficacy data across eligible cohorts, with a primary objective of estimating the proportion of pts with an undetectable PSA at 12 months within each cohort. Secondary objectives include safety, proportion of patients with ≥50% decline in PSA from baseline and quality of life measures. Correlative studies will assess blood and tissue molecular biomarkers for association with outcomes. The study is open with two patients enrolled at the time of abstract submission. Clinical trial information: NCT04336943.
External validation of the VIGex gene-expression signature (GES) as a novel predictive biomarker for immune checkpoint treatment (ICT).
Authors: Alberto Hernando-Calvo, S Y Cindy Yang, Maria Vila-Casadesús, Hal K. Berman, Anna Spreafico, Albiruni Ryan Abdul Razak, Stephanie Lheureux, Aaron Richard Hansen, Deborah Lo Giacco, Judit Matito, Trevor John Pugh, Scott Victor Bratman, Roger Berché, Omar Saavedra Santa Gadea, Elena Garralda, Sawako Elston, Lillian L. Siu, Pamela S. Ohashi, Ana Vivancos, Philippe L. Bedard
Journal: Journal of Clinical Oncology (2022)

2510 Background: VIGex is a 12- gene GES classifier initially developed on the Nanostring platform and validated for RNA-seq. VIGex classifies samples into Hot, intermediate-Cold (I-Cold) and Cold subgroups. The Hot subgroup as defined by VIGex has been associated with better (PFS) in patients (pts) treated on phase 1 ICT trials at Vall D’Hebron Hospital (VH) (ESMO2020). We investigated the performance of VIGex in pts treated with Pembrolizumab (P) in the INSPIRE clinical trial (NCT02644369) at Princess Margaret Cancer Centre (PM) and compared VIGex with other predictive ICT biomarkers. Methods: Pts with advanced solid tumors were treated with P 200 mg IV Q3wks. RNA-seq from baseline biopsies was performed using the Illumina NextSeq550 platform. Tumor RNA-seq data were transferred from PM to VH and classified by the VIGex algorithm blinded to clinical data. Bespoke circulating tumor DNA (ctDNA) was assayed at baseline (B) and start of cycle 3 (C3) using a pt-specific amplicon-based NGS assay (Signatera). Tumor mutational burden (TMB) was defined as the number of non-synonymous mutations per megabase and PD-L1 was assessed by immunohistochemistry (22C3). Hot subgroup (HOT) was compared to I-Cold + Cold (COLD). We defined 4 groups based on the combination of VIGex subgroups and the change in ctDNA at cycle 3 from baseline (ΔctDNA). Survival times were calculated with the Kaplan–Meier method and Cox proportional-hazard models were constructed. Results: Out of 76 pts, median age was 55y (range 21-81y), M:F 31:45, all ECOG 0-1, 16 High-grade serous ovarian, 12 triple negative breast, 12 head and neck, 10 melanoma and 26 other. Median no. of P cycles was 3 (range 1–35); follow up was 14m (range 1-67); Median PFS 10.9m and median overall survival (OS) 14m. Overall response rate (RECIST 1.1) was 24% in HOT and 10% in COLD (p = 0.22 two-sided Fisher's exact test). The HOT subgroup was significantly associated with higher OS and PFS when included in a multivariate model adjusted by tumor histology, TMB and PD-L1 (HR 0.43; 95%CI 0.23-0.81; p = 0.009) and (HR: 0.48; 95%CI 0.25-0.95; p = 0.036) respectively. A total of 57 pts had both VIGex and ΔctDNA data. The addition of ΔctDNA further improved the predictive performance of VIGex for OS (Table). Conclusions: VIGex maintained its predictive power for ICT outcomes when applied to an independent external dataset using RNA-seq. The predictive information provided by VIGex was independent of PD-L1 and TMB. Our data indicates that the addition of ΔctDNA to baseline VIGex may refine prediction for ICT outcomes. [Table: see text]
Artificial light pollution and obesity as a risk factors of malignant cardiac arrhythmias - antiarrhythmogenic effect of omacor
Authors: B Szeiffova Bacova, M Sykora, T Egan Benova, J Zurmanova, K Andelova, N Tribulova
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: None. Light pollution disrupts circadian rhythms and increases the development of obesity, but their connection to cardiovascular disease, in particular to malignant arrhythmias, is not well known. Herein, we investigated if female rats exposed to continuous light and high-sucrose diet had altered myocardial gene transcripts and/or protein expression which affects arrhythmogenesis. We then assessed if Omacor® supplementation benefitted affected rats. In a first experiment, adult female spontaneously hypertensive (SHR) and normotensive Wistar rats (WR) were housed under standard 12 h/12 h light/dark cycles or exposed to 6-weeks continuous 300 lux light for 24 h. In a second experiment, adult female WR rats received sucrose diet (30% sucrose solution) continuously (24 h) performed for 8 weeks. Half the rats from both experiments were throughout the experiment treated with 200 mg/100g b.w. Omacor®. Continuous light resulted in higher rat vulnerability to malignant ventricular fibrillation (VF). This was linked with myocardial connexin-43 (Cx43) down-regulation and deteriorated intercellular electrical coupling, due in part to increased pro-inflammatory NF-κB and iNOS transcripts and decreased sarcoplasmic reticulum Ca 2+ ATPase transcripts. Omacor® treatment increased the electrical threshold to induce the VF linked with amelioration of myocardial Cx43 mRNA and Cx43 protein levels and the suppression of NF-κB and iNOS. 8 weeks lasting intake of 30% sucrose solution downregulated Cx43 and PKCε signaling along with an upregulation of myocardial PKCδ and miR-30a rendering the heart prone to ventricular arrhythmias. There was a clear benefit of Omacor® supplementation due to their antiarrhythmic effects associated with the attenuation of myocardial Cx43, PKC, and miR-30a abnormalities. This indicates that rat exposure to continuous light and high-sucrose result in deleterious cardiac alterations jeopardizing intercellular Cx43 channel-mediated electrical communication, thereby increasing the risk of malignant arrhythmias. The adverse effects were attenuated by treatment with Omacor®, thus supporting its potential benefit and the relevance of monitoring omega-3 index in human populations at risk.
p57Kip2 regulates embryonic blood stem cells by controlling sympathoadrenal progenitor expansion
Authors: Chrysa Kapeni, Leslie Nitsche, Alastair M. Kilpatrick, Nicola K. Wilson, Kankan Xia, Bahar Mirshekar-Syahkal, Vashe Chandrakanthan, Camille Malouf, John E. Pimanda, Berthold Göttgens, Kristina Kirschner, Simon R. Tomlinson, Katrin Ottersbach
Journal: Blood (2022)

Hematopoietic stem cells (HSCs) are of major clinical importance, and finding methods for their in vitro generation is a prime research focus. We show here that the cell cycle inhibitor p57Kip2/Cdkn1c limits the number of emerging HSCs by restricting the size of the sympathetic nervous system (SNS) and the amount of HSC-supportive catecholamines secreted by these cells. This regulation occurs at the SNS progenitor level and is in contrast to the cell-intrinsic function of p57Kip2 in maintaining adult HSCs, highlighting profound differences in cell cycle requirements of adult HSCs compared with their embryonic counterparts. Furthermore, this effect is specific to the aorta-gonad-mesonephros (AGM) region and shows that the AGM is the main contributor to early fetal liver colonization, as early fetal liver HSC numbers are equally affected. Using a range of antagonists in vivo, we show a requirement for intact β2-adrenergic signaling for SNS-dependent HSC expansion. To gain further molecular insights, we have generated a single-cell RNA-sequencing data set of all Ngfr+ sympathoadrenal cells around the dorsal aorta to dissect their differentiation pathway. Importantly, this not only defined the relevant p57Kip2-expressing SNS progenitor stage but also revealed that some neural crest cells, upon arrival at the aorta, are able to take an alternative differentiation pathway, giving rise to a subset of ventrally restricted mesenchymal cells that express important HSC-supportive factors. Neural crest cells thus appear to contribute to the AGM HSC niche via 2 different mechanisms: SNS-mediated catecholamine secretion and HSC-supportive mesenchymal cell production.
Transperineal versus transrectal targeted prostate biopsy: A multicenter matched pairs study of the Turkish Urooncology Association
Authors: M.Y. Koparal, T.S. Sözen, N. Karşıyakalı, G. Aslan, B. Akdoğan, B. Şahin, L. Türkeri
Journal: European Urology (2022)
NFB-04. Evaluating focal areas of signal intensity (FASI) in children with neurofibromatosis type-1 (NF1) treated with selumetinib on PBTC-029B
Authors: Natasha Pillay Smiley, James Leach, Adam Lane, Trent Hummel, Jason Fangusaro, Peter de Blank
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Focal Areas of Signal Intensity (FASI) are T2 hyperintense benign lesions in children with NF1. They can mimic the appearance of low-grade glioma (LGG). Selumetinib has shown efficacy in treatment of NF1-associated LGG but treatment effects on FASI have not yet been described. METHODS: Patients with NF1-associated LGG treated with selumetinib on Stratum 3 of PBTC-029B were compared to age-matched untreated children with NF1-associated LGG at Cincinnati Children’s Hospital Medical. FASI were defined by published criteria as T2 hyperintense lesions lacking mass effect, enhancement or T1 hypointensity. Lesion size was determined by cross-product of perpendicular measures in LGG and 1-3 FASI per subject. When multiple FASI were present, the sum of FASI cross-products was used. Change between baseline and the latest available measure within 4 months of control was assessed, insuring that selumetinib-treated subjects were still receiving therapy. RESULTS: Fifteen age-matched pairs were assessed (2.8-16.9 years and 60% were male). Initial FASI size was not different between groups (p=0.98; median [IQR]: 138.7mm2 [88.4-182.0] for treated subjects versus 121.6mm2 [79.6-181.9] for untreated subjects). Lesion change was measured over mean follow up of 18.9 + 5.9 months. Spider plots show decreased LGG size over time during treatment, but there was no consistent change in size among treated or untreated FASI. Comparing FASI size between paired timepoints showed no difference in change from baseline for treated subjects versus for untreated subjects (two-sided test; p=0.08). In subjects who received selumetinib, there was no correlation between change in LGG and change in FASI (r=-0.04, p=0.88). Using RANO criteria for FASI lesions, 2/30 (6.7%) subjects had partial response, 26/30 (86.7%) subjects had stable disease, and 2/30 (6.7%) subjects had progressive disease. CONCLUSIONS: While the sample size was limited, treatment with selumetinib did not reduce overall FASI size in children with NF1 and LGG.
The 2021 EULAR/American College of Rheumatology points to consider for diagnosis, management and monitoring of the interleukin-1 mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes, tumour necrosis factor receptor-associated periodic syndrome, mevalonate kinase deficiency, and deficiency of the interleukin-1 receptor antagonist
Authors: Micol Romano, Z Serap Arici, David Piskin, Sara Alehashemi, Daniel Aletaha, Karyl S Barron, Susanne Benseler, Roberta Berard, Lori Broderick, Fatma Dedeoglu, Michelle Diebold, Karen L Durrant, Polly Ferguson, Dirk Foell, Jonathan Hausmann, Olcay Y Jones, Daniel L Kastner, Helen J Lachmann, Ronald M Laxer, Dorelia Rivera, Nicolino Ruperto, Anna Simon, Marinka Twilt, Joost Frenkel, Hal Hoffman, Adriana A de Jesus, Jasmin Beate Kuemmerle-Deschner, Seza Ozen, Marco Gattorno, Raphaela Goldbach-Mansky, Erkan Demirkaya
Journal: Annals of the Rheumatic Diseases (2022)

<h3>Background</h3> The interleukin-1 (IL-1) mediated systemic autoinflammatory diseases, including the cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD) and deficiency of the IL-1 receptor antagonist (DIRA), belong to a group of rare immunodysregulatory diseases that primarily present in early childhood with variable multiorgan involvement. When untreated, patients with severe clinical phenotypes have a poor prognosis, and diagnosis and management of these patients can be challenging. However, approved treatments targeting the proinflammatory cytokine IL-1 have been life changing and have significantly improved patient outcomes. <h3>Objective</h3> To establish evidence-based recommendations for diagnosis, treatment and monitoring of patients with IL-1 mediated autoinflammatory diseases to standardise their management. <h3>Methods</h3> A multinational, multidisciplinary task force consisting of physician experts, including rheumatologists, patients or caregivers and allied healthcare professionals, was established. Evidence synthesis, including systematic literature review and expert consensus (Delphi) via surveys, was conducted. Consensus methodology was used to formulate and vote on statements to guide optimal patient care. <h3>Results</h3> The task force devised five overarching principles, 14 statements related to diagnosis, 10 on therapy, and nine focused on long-term monitoring that were evidence and/or consensus-based for patients with IL-1 mediated diseases. An outline was developed for disease-specific monitoring of inflammation-induced organ damage progression and reported treatments of CAPS, TRAPS, MKD and DIRA. <h3>Conclusion</h3> The 2021 EULAR/American College of Rheumatology points to consider represent state-of-the-art knowledge based on published data and expert opinion to guide diagnostic evaluation, treatment and monitoring of patients with CAPS, TRAPS, MKD and DIRA, and to standardise and improve care, quality of life and disease outcomes.